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© 2002 American Society for Clinical Oncology Granulocyte Colony-Stimulating Factor in Induction Treatment of Children With Non-Hodgkin’s Lymphoma: A Randomized Study of the French Society of Pediatric OncologyByFrom the Departments of Pediatrics and Statistics, Institut Gustave Roussy, Villejuif; Onco-Hematology Pediatrics Department, Hôpital Purpan, Centre Hospitalier Universitaire, Toulouse; Pediatric Hematology Department, Hôpital St-Louis, and Pediatrics Department, Institut Curie, Paris; Pediatrics Department, Centre Léon Bérard, Lyon; Onco-Hematology Pediatrics Department, Hôpital Brabois, Centre Hospitalier Universitaire, Nancy; Onco-Hematology Pediatrics Department, Centre Hospitalier Universitaire, Nantes; Onco-Hematology Pediatrics Department, Centre Hospitalier Universitaire, Lille; and Onco-Hematology Pediatrics Department, Centre Hospitalier Universitaire, Caen, France. Address reprint requests to Catherine Patte, MD, Pediatrics Department, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France; email: patte{at}.igr.fr
PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF; lenograstim) decreases the incidence of febrile neutropenia after induction courses in treatment of childhood non-Hodgkin’s lymphoma (NHL).
PATIENTS AND METHODS: Patients were randomized to receive (G-CSF+) or not receive (G-CSF-) prophylactic G-CSF, 5 µg/kg/d, from day 7 until an absolute neutrophil count RESULTS: One hundred forty-eight patients were assessable, 75 G-CSF+ and 73 G-CSF-. Although duration of neutropenia less than 500/µL was 3 days shorter in G-CSF+ patients (P = 10-4), incidence of febrile neutropenia (89% v 93% in the first course, 88% v 88% in the second course), durations of hospitalization and antimicrobial therapy, percentages of infections, mucositis, and transfusions were not significantly different. Although the percentage of G-CSF+ patients commencing the following course on day 21 was significantly higher (84% v 68% after the first and 57% v 38% after the second course; P < .05), the median delay between the two courses was only 1 day less in G-CSF+ patients (median delay after first COPAD(M), 19 v 20 days, P = .01; after second, 21 v 22 days, P = not significant). Remission and survival rates were similar in both arms. CONCLUSION: This study demonstrates that G-CSF did not decrease treatment-related morbidity, nor increase the dose-intensity in children undergoing COPAD(M) induction chemotherapy for NHL.
THE PROGNOSIS OF children with non-Hodgkin’s lymphoma, especially Burkitt’s lymphoma, has improved significantly over the past two decades with the introduction of intensive chemotherapy protocols adapted to histologic and immunology subtypes.1-7 In the French Society of Pediatric Oncology (SFOP) protocols for non-Hodgkin’s lymphoma, the induction phase, based on the regimen of cyclophosphamide, vincristine, prednisone, doxorubicin, and high-dose methotrexate (COPAD[M]), is associated with high morbidity from neutropenic fever and mucositis that require hospitalization in more than 80% of patients.1,2 Consequent life-threatening infections and delays between courses may adversely influence treatment outcome. Recombinant hematopoietic colony-stimulating factors that stimulate recovery from granulocytopenia could reduce infectious complications of myelotoxic cancer treatment and delays in starting courses. Many studies in adults with solid tumors,8-15 lymphomas,16-19 or acute lymphoblastic leukemia20-22 have shown the biologic effects of granulocyte colony-stimulating factor (G-CSF), although improvement in the incidence of febrile neutropenia and infections, the duration of hospitalization and antibiotics, and the delay in the administration of the following chemotherapy course has not been reliable.23-25 One study showed a reduction in mucositis.12 Randomized studies in children are less numerous, and those conducted mainly concern lymphoblastic leukemia,26-31 sarcomas,32 and neuroblastomas.33 In January 1994, the SFOP initiated a multicentric, randomized, nonblinded trial to determine whether G-CSF use had a clinical and economic impact on the induction phase of treatment in children with non-Hodgkin’s lymphoma. The primary aim of the study was to assess the effect of G-CSF on the incidence of febrile neutropenia and consequent hospitalization. A placebo-controlled trial with subcutaneous administration of a placebo was judged unacceptable in child patients by the majority of clinicians, because assessment criteria were considered objective. We report herein the final results of this prospective trial, which accrued 149 patients.
Patient Characteristics The trial was open to the SFOP French cancer treatment centers. Patients with non-Hodgkin’s lymphoma included in one of the three ongoing SFOP protocols (LMB89 for B-cell lymphomas, LMT89 for lymphoblastic and other T-cell lymphomas, and HM91 for anaplastic large-cell lymphoma) were eligible. COPAD(M) courses were part of the induction phase of these protocols. Children presenting with fever or a known infection, in need of gastrointestinal tract decontamination with absorbable antibiotics, or already undergoing G-CSF treatment were not included, nor were children infected with human immunodeficiency virus or presenting immunodeficiency or who had had a previous cancer. Only oral prophylactic antibiotics for gut decontamination with nonabsorbable antibiotics was allowed. It was recommended that oral trimethoprim and sulfamethoxazole be started after completion of the COPAD(M) courses. All parents gave their written informed consent before randomization. The study protocol was approved by the ethical committee for the protection of persons undergoing biomedical research.
Treatment Protocol
Patients were to receive two consecutive courses of COPAD(M). The second course was to be started when an absolute neutrophil count (ANC) of  1,500/µL and platelets 100,000/µL were reached. The minimum interval was 16 days.
Randomization and G-CSF Treatment
End Points and Clinical Follow-Up The primary end point was the incidence of febrile neutropenia. Fever was defined as a central (axillary) temperature 38°5 (38°) once or more than 38° (37°5) on three occasions within 24 hours. Neutropenia was defined as an ANC of less than 500/µL. The secondary objectives were the incidence of severe infections; the duration of neutropenia, fever, hospitalization, and antibiotics; the incidence of grade 3 and 4 mucositis and of thrombocytopenia (< 50,000/µL); the number of RBC and platelet transfusions; and the complete remission and overall and event-free survival rates at 1 and 2 years. Infections were classified as (1) severe (World Health Organization grade 3 and 4), ie, urinary tract infection with clinical symptoms, cellulitis, pneumonia, bacteremia (except Staphylococcus epidermidis), septic shock with hypotension, or disseminated fungal infection; (2) bacteremia with S epidermidis; (3) mild to moderate (World Health Organization grade 1 and 2); (4) fever of an unknown origin, ie, fever with no clinical or culture documentation. All data collected were systematically controlled to guarantee their quality. The evaluation of hospitalization, G-CSF, laboratory, and transfusion costs was planned and has been reported in a separate article.34
Management of Fever and Neutropenia
Statistical Analysis Results are expressed as percentages, means, and the SD or medians (range). Overall and event-free survival rates were calculated using the Kaplan-Meier method36 and Rothman’s confidence intervals (95% CI).37 Survival curves were compared using the log-rank test.38 Nonadjusted P values are presented because conclusions remained unchanged when the stratification factors were taken into account. We performed an intention-to-treat analysis. All tests are two-sided.
Patient Characteristics A total of 149 patients treated in 28 French centers were enrolled onto the study from January 1994 to June 1996. One patient was excluded because of a major protocol violation. She was randomly assigned to the control group with the diagnosis of a pelvic abscess, and G-CSF was administered in a modified chemotherapy course. One hundred forty-eight patients were therefore analyzed, 75 in the G-CSF arm and 73 in the control arm. Initial patient characteristics are presented in Table 2. The two groups were similar in terms of age, sex, primary site, stage, and protocol.
Treatment With G-CSF and Neutropenia Five major protocol deviations were observed: G-CSF was administered for only 1 day in one patient in the G-CSF group (a parental decision), and four patients in the control group received G-CSF because of a severe clinical status or infection during aplasia after the first course. If the first patient is not taken into account, the median duration of treatment with G-CSF was 8 days (range, 6 to 13 days) after the first COPAD(M) course and 9 (range, 3 to 17 days) after the second course. G-CSF was stopped on day 3 in one patient because the ANC had reached greater than 20,000/µL and on day 17 in two patients when the ANC was 500/µL over 48 hours. As planned in the protocol, G-CSF was stopped on day 15 in one patient, although he was still febrile with a WBC count of 110/µL. He became afebrile on day 25 and the ANC had increased to greater than 500/µL by day 28. The incidence of neutropenia was not significantly different between the two arms; however, its duration was significantly shorter in the G-CSF as compared with the control group (Table 3).
Febrile Neutropenia, Hospitalization, and Supportive Care The incidence of febrile neutropenia did not differ significantly between the two groups: 89% in the G-CSF group and 93% in the control group after the first course of COPAD(M) and 88% in both groups after the second course. The duration of hospitalization and parenteral antibiotics was only 1 day shorter in the G-CSF group after each course, and was not significantly different, except for the duration of antibiotics, after the second course (Table 3). The use of systemic fungal therapy was less frequent in the G-CSF group after the first course of induction therapy (16% v 33%; P = .02) but was not different after the second course (24% v 29%; P = not significant). The distribution of the types of infection was not different between the two groups (Table 4), especially in the case of severe infections, with seven in the G-CSF group and 10 in the control group after the first COPAD(M) course and 10 in the G-CSF group and seven in the control group after the second COPAD(M) course. No fungal infection was documented. No death related to infection occurred. The incidence of grade 3 and 4 mucositis was similar in both arms, as were the number of RBC and platelet transfusions (Table 3). These results were not influenced by the fact that a few patients received nonabsorbable oral antibiotics for gut decontamination, nor by the time to the initiation of intravenous antifungal therapy (equally distributed in each group).
Lymphoma Treatment and Outcome Although a significantly higher percentage of patients in the G-CSF group (84% v 68% and 57% v 38% after the first and the second courses, respectively; P < .05) began the following course on day 21, the median delay between the two consecutive courses was only 1 day shorter among G-CSF patients as compared with control patients. The median delay between the first and second COPAD(M) courses was 19 days (range, 14 to 31 days) in the G-CSF group compared with 20 days (range, 14 to 42 days) in the control group (P = .01), and median delay between the second and the following course was 21 days (range, 17 to 60 days) in the G-CSF group compared with 22 days (range, 16 to 40 days) in the control group (P = not significant). The complete remission rate after the second course and at the time of remission assessment was similar in both groups. Treatment failed in six patients because of refractory primary disease (n = 1) and relapse (n = 2) in the G-CSF arm, and relapse in the control arm (n = 3). Seven deaths occurred: four in the G-CSF arm (three treatment failures and one unrelated to lymphoma or treatment) and three in the control arm (one patient died with hemorrhagic cerebral symptoms after the first course and two patients experienced relapse). Overall and event-free survival rates were similar in both groups (Fig 2).
In this large series of children treated with COPAD(M) intensive induction therapy for non-Hodgkin’s lymphoma and randomly assigned to receive or not receive prophylactic G-CSF, we demonstrated a G-CSF–induced biologic effect that led to faster recovery from neutropenia. However, this biologic effect was not translated into clinical advantages, because G-CSF did not decrease the rate of febrile neutropenia (the first study end point) and consequent hospitalization, nor did it decrease the rate of severe infections. Furthermore, it did not significantly reduce the duration of hospitalization and antibiotic use. No infection-related death, possibly linked to the absence of G-CSF, was observed in the control group. The percentage of patients who received the following course at day 21 was higher in G-CSF group, but only one day was gained on average. Remission and event-free survival rates were similar in both groups, indicating that G-CSF neither promoted tumor proliferation (an adverse effect) nor markedly shortened the delay between courses (a beneficial effect). Our study is not a placebo-controlled study, which is always the best way to guarantee the absence of a bias. We chose not to administer a placebo because the subcutaneous route of administration was considered unethical by many of us and because we thought that the main criterion, febrile neutropenia, and many of the other criteria, which were biologic values, were objective. These results were obtained with the glycosylated form of the recombinant human G-CSF (lenograstim). Although it differs biologically in vitro from the nonglycosylated form (filgrastim),39 to date no clinical study has shown relevant differences between them in term of efficacy and the toxicity profile.40 Likewise, although G-SCF and granulocyte-macrophage colony-stimulating factor (GM-CSF) are not similar cytokines, they are equally efficient against neutropenia induced by conventional chemotherapy.41,42 It is also noteworthy that G-CSF and GM-CSF are considered together in American Society of Clinical Oncology recommendations.43-45 Consequently, in the following discussion, studies will be reported using either of these cytokines. The duration of neutropenia was reduced in the courses in this study to a similar extent as that observed in other randomized studies performed in adults or children receiving conventional chemotherapy with G-CSF or GM-CSF. However, this biologic effect was not consistently converted into clinical effects; some studies demonstrated a benefit while others did not. Such contradictory results are in fact related to the end points chosen or the parameters studied. They are also linked to differences in the intensity of the chemotherapy regimens, in schedules, and in the type of drugs and their dose. As in our study, it seems that for regimens containing an alkylating agent at an intermediate dose (especially cyclophosphamide between 1.5 and 4 g/m2), G-CSF does not seem to reduce the incidence of febrile neutropenia, as neutropenia is profound and of short duration. In contrast, regimens with etoposide or other nonalkylating agents seem to benefit from the use of G-CSF or GM-CSF. This was demonstrated in two trials. In the first, which focused on 59 patients with metastatic neuroblastoma, the incidence of febrile neutropenia was reduced after the cisplatin and etoposide courses but not after a course that combined vincristine, cyclophosphamide, and doxorubicin.33 In the second trial of 67 patients with high-risk acute lymphocytic leukemia treated with significantly dose-intense chemotherapy, the duration of fever, antibiotics, and hospitalization decreased significantly after the R3 course, which included high-dose cytarabine, etoposide, and dexamethasone, but not after the modified COPAD(M) courses.29 Results were similar in a study alternating vincristine, doxorubicin, and cyclophosphamide with ifosfamide and etoposide in 37 children with sarcomas.32 Few randomized trials have been published on the use of G-CSF in pediatric lymphomas. One concerned 33 patients with lymphoblastic lymphoma included in the same study along with 56 patients with T-cell lymphoblastic leukemia. It showed that supportive therapy with G-CSF may be unnecessary for short-lived neutropenia.28 Another study involved 19 children and 15 adults with high-risk small noncleaved cell lymphoma included in the same study and treated with an intensive short duration regimen that was similar to ours. In this study, GM-CSF failed to reduce the duration of neutropenia and neutropenia-related complications but significantly prolonged thrombocytopenia.6 In our study, although the need for platelet transfusion was greater in the G-CSF arm, it was not significantly different from that of the control arm. However, this parameter was found to be significant in other studies.13,24,32 Our study included a cost evaluation that has been published elsewhere.34 In our study setting and with the current prices in France, significant differences were not found between the two arms. The expenditure reported may differ in other countries with different costs for hospitalization and drugs. The cost of 2 more days of hospitalization in the control group must be weighed against the price of 17 days of G-CSF. Likewise, our findings and conclusions regarding data on infections and antibiotics may be different in other countries with other bacterial problems and other possibilities for supportive care and therefore must be reinterpreted according to specific environments. In conclusion, although it has been recognized that the use of G-CSF or of GM-CSF is beneficial in the high-dose chemotherapy setting with hematopoietic stem-cell transplantation, our results challenge the widespread recommendation of the use of G-CSF in the conventional chemotherapy setting. Indeed we do not show any clinical benefit of G-CSF use after a chemotherapy regimen like COPAD(M), which induces a high incidence of febrile neutropenia.
APPENDIX
Supported in part by Roger Bellon, Neuilly-sur-Seine, and by Programme Hospitalier de Recherche Clinique de 1994, Direction Départementale des Affaires Sanitaires et Sociales du Val de Marne, France. We thank N. Dupouy for data management; J.P. Mamet, C. Rubino, and L. Foix for their assistance; and L. Saint-Ange for editing.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
